Endothelial damage in septic shock patients as evidenced by circulating syndecan-1, sphingosine-1-phosphate and soluble VE-cadherin: a substudy of ALBIOS.

BACKGROUND: Septic shock is characterized by breakdown of the endothelial glycocalyx and endothelial damage, contributing to fluid extravasation, organ failure and death. Albumin has shown benefit in septic shock patients. Our aims were: (1) to identify the relations between circulating levels of syndecan-1 (SYN-1), sphingosine-1-phosphate (S1P) (endothelial glycocalyx), and VE-cadherin (endothelial cell junctions), severity of the disease, and survival; (2) to evaluate the effects of albumin supplementation on endothelial dysfunction in patients with septic shock. METHODS: This was a retrospective analysis of a multicenter randomized clinical trial on albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis Trial, ALBIOS). Concentrations of SYN-1, S1P, soluble VE-cadherin and other biomarkers were measured on days 1, 2 and 7 in 375 patients with septic shock surviving up to 7 days after randomization. RESULTS: Plasma concentrations of SYN-1 and VE-cadherin rose significantly over 7 days. SYN-1 and VE-cadherin were elevated in patients with organ failure, and S1P levels were lower. SYN-1 and VE-cadherin were independently associated with renal replacement therapy requirement during ICU stay, but only SYN-1 predicted its new occurrence. Both SYN-1 and S1P, but not VE-cadherin, predicted incident coagulation failure. Only SYN-1 independently predicted 90-day mortality. Albumin significantly reduced VE-cadherin, by 9.5% (p = 0.003) at all three time points. CONCLUSION: Circulating components of the endothelial glycocalyx and of the endothelial cell junctions provide insights into severity and progression of septic shock, with special focus on incident coagulation and renal failure. Albumin supplementation lowered circulating VE-cadherin consistently over time. CLINICAL TRIAL REGISTRATION: ALBIOS ClinicalTrials.gov number NCT00707122.

Assisted mechanical ventilation promotes recovery of diaphragmatic thickness in critically ill patients: a prospective observational study.

BACKGROUND: Diaphragm atrophy and dysfunction are consequences of mechanical ventilation and are determinants of clinical outcomes. We hypothesize that partial preservation of diaphragm function, such as during assisted modes of ventilation, will restore diaphragm thickness. We also aim to correlate the changes in diaphragm thickness and function to outcomes and clinical factors. METHODS: This is a prospective, multicentre, observational study. Patients mechanically ventilated for more than 48 h in controlled mode and eventually switched to assisted ventilation were enrolled. Diaphragm ultrasound and clinical data collection were performed every 48 h until discharge or death. A threshold of 10% was used to define thinning during controlled and recovery of thickness during assisted ventilation. Patients were also classified based on the level of diaphragm activity during assisted ventilation. We evaluated the association between changes in diaphragm thickness and activity and clinical outcomes and data, such as ventilation parameters. RESULTS: Sixty-two patients ventilated in controlled mode and then switched to the assisted mode of ventilation were enrolled. Diaphragm thickness significantly decreased during controlled ventilation (1.84 ± 0.44 to 1.49 ± 0.37 mm, p < 0.001) and was partially restored during assisted ventilation (1.49 ± 0.37 to 1.75 ± 0.43 mm, p < 0.001). A diaphragm thinning of more than 10% was associated with longer duration of controlled ventilation (10 [5, 15] versus 5 [4, 8.5] days, p = 0.004) and higher PEEP levels (12.6 ± 4 versus 10.4 ± 4 cmH2O, p = 0.034). An increase in diaphragm thickness of more than 10% during assisted ventilation was not associated with any clinical outcome but with lower respiratory rate (16.7 ± 3.2 versus 19.2 ± 4 bpm, p = 0.019) and Rapid Shallow Breathing Index (37 ± 11 versus 44 ± 13, p = 0.029) and with higher Pressure Muscle Index (2 [0.5, 3] versus 0.4 [0, 1.9], p = 0.024). Change in diaphragm thickness was not related to diaphragm function expressed as diaphragm thickening fraction. CONCLUSION: Mode of ventilation affects diaphragm thickness, and preservation of diaphragmatic contraction, as during assisted modes, can partially reverse the muscle atrophy process. Avoiding a strenuous inspiratory work, as measured by Rapid Shallow Breathing Index and Pressure Muscle Index, may help diaphragm thickness restoration.

Regional blood acidification enhances extracorporeal carbon dioxide removal: a 48-hour animal study.

BACKGROUND: Extracorporeal carbon dioxide removal has been proposed to achieve protective ventilation in patients at risk for ventilator-induced lung injury. In an acute study, the authors previously described an extracorporeal carbon dioxide removal technique enhanced by regional extracorporeal blood acidification. The current study evaluates efficacy and feasibility of such technology applied for 48 h. METHODS: Ten pigs were connected to a low-flow veno-venous extracorporeal circuit (blood flow rate, 0.25 l/min) including a membrane lung. Blood acidification was achieved in eight pigs by continuous infusion of 2.5 mEq/min of lactic acid at the membrane lung inlet. The acid infusion was interrupted for 1 h at the 24 and 48 h. Two control pigs did not receive acidification. At baseline and every 8 h thereafter, the authors measured blood lactate, gases, chemistry, and the amount of carbon dioxide removed by the membrane lung (VCO2ML). The authors also measured erythrocyte metabolites and selected cytokines. Histological and metalloproteinases analyses were performed on selected organs. RESULTS: Blood acidification consistently increased VCO2ML by 62 to 78%, from 79 ± 13 to 128 ± 22 ml/min at baseline, from 60 ± 8 to 101 ± 16 ml/min at 24 h, and from 54 ± 6 to 96 ± 16 ml/min at 48 h. During regional acidification, arterial pH decreased slightly (average reduction, 0.04), whereas arterial lactate remained lower than 4 mEq/l. No sign of organ and erythrocyte damage was recorded. CONCLUSION: Infusion of lactic acid at the membrane lung inlet consistently increased VCO2ML providing a safe removal of carbon dioxide from only 250 ml/min extracorporeal blood flow in amounts equivalent to 50% production of an adult man.

Long term outcome in patients treated with veno-venous extracorporeal membrane oxygenation: A prospective observational study.

INTRODUCTION: Over the last few decades, the use of veno-venous extracorporeal membrane oxygenation (VV-ECMO) support for severe respiratory failure has increased. AIM: This study aimed to assess the long-term outcomes of patients treated with VV-ECMO for respiratory failure. METHODS: We performed a single-centre prospective evaluation of patients on VV-ECMO who were successfully discharged from the intensive care unit of an Italian University Hospital between January 2018 and May 2021. The enrolled patients underwent follow-up evaluations at 6 and 12 months after ICU discharge. The follow-up team performed psychological and functional assessments using the following instruments: Hospital Anxiety and Depression Scale (HADS), Post-traumatic Stress Disorder Symptom Severity Scale (PTSS-10), Euro Quality Five Domains Five Levels (EQ-5L-5D), and 6-minute walk test. RESULTS: We enrolled 33 patients who were evaluated at a follow-up clinic. The median patient age was 51 years (range: 45-58 years). The median duration of VV-ECMO support was 12 (9-19) days and the length of ICU stay was 23 (18-42) days. A HADS score higher than 14 was reported in 8 (24 %) and 7 (21 %) patients at the six- and twelve-month visit, respectively. PTSS-10 total score ≥ 35 points was present in three (9 %) and two (6 %) patients at the six- and twelve-month examination. The median EQ-5L-5D-VAS was respectively 80 (80-90) and 87.5 (70-95). The PTSS-10 score significantly decreased from six to 12 months in COVID-19 survivors (p = 0.024). CONCLUSIONS: In this cohort of patients treated with VV-ECMO, cognitive and psychological outcomes were good and comparable to those of patients with Adult Respiratory Distress Syndrome (ARDS) managed without ECMO. IMPLICATIONS FOR CLINICAL PRACTICE: The findings of this study confirm the need for long-term follow-up and rehabilitation programs for every ICU survivor after discharge. COVID-19 survivors treated with VV-ECMO had outcomes comparable to those reported in non-COVID patients.

Long-Term Physical, Cognitive, and Psychological Outcomes in Severe COVID-19 Patients Managed With Extracorporeal Membrane Oxygenation: A Prospective Study.

Extracorporeal membrane oxygenation (ECMO) has been used in highly selected COVID-19 patients with severe respiratory failure. Scarce data exist on long-term outcomes of these patients. We performed a single-center prospective evaluation of consecutive COVID-19 ECMO patients successfully discharged from the intensive care unit between February 2020 and January 2022. Physical, cognitive and psychological outcome was assessed at 3, 6, and 12 months by in-person evaluation. All the 34 discharged patients (median age 49 years old) were alive at one year, and 25 of them were evaluated at the follow-up clinic. 67% of patients had muscle weakness, with improvement over time (p = 0.032). The percentage of patients able to return to work progressively increased, up to 86% at 1 year. 23% of patients experienced fatigue. Participation restriction improved over time for both physical (p = 0.050) and emotional (p = 0.005) problems. Cognitive impairment, anxiety, and depression occurred in 29%, 29%, and 23% of patients, respectively, with no changes over time. Health-related quality of life was good. In conclusion, COVID-19 ECMO patients suffer from significant long-term sequelae. However, multidimensional outcomes continued to improve over the follow-up time.

Hospital Memories and Six-Month Psychological Outcome: A Prospective Study in Critical Ill Patients with COVID-19 Respiratory Failure.

ICU survivors suffer from various long-term physical and psychological impairments. Memories from the critical illness may influence long-term psychological outcome. In particular, the role of ICU memories in COVID-19 critically ill patients is unknown. In a prospective observational study, we aimed to investigate patients' memories from the experience of critical illness and their association with a six-month psychological outcome involving quality of life evaluation. Patients' memories were investigated with ICU Memory tool, while psychological outcome and quality of life were evaluated by means of a battery of validated questionnaires during an in-person interview at the follow-up clinic. 149 adult patients were enrolled. 60% retained memories from pre-ICU days spent on a general ward, while 70% reported memories from the in-ICU period. Delusional memories (i.e., memories of facts that never happened) were reported by 69% of patients. According to a multivariable analysis, the lack of pre-ICU memories was an independent predictor of worse psychological outcomes in terms of anxiety, depression and Post-traumatic Stress Disorder (PTDS). Factors associated with long-term outcome in ICU survivors are not still fully understood and patients' experience during the day spent before ICU admission may be associated with psychological sequelae.

Implementation of a Follow-Up Program for Intensive Care Unit Survivors.

In Intensive Care Unit (ICU) survivors, critical illness has an impact on an individual's long-term health status and quality of life. Adults who have recovered from intensive care management could develop muscle weakness, neurocognitive impairment, difficulties in managing activities of daily living and to returning to work, and psychological problems such as depression and anxiety. A prospective, observational study was designed. Data were collected from January to December 2018 from a structured follow-up program, at 3 time points after ICU discharge: at seven days, a visit in the general ward, a phone interview at three months and an ambulatory visit at six months. A total of 95 patients were enrolled, 36% female, with a median age of 65 (55-73) years and a median ICU length of stay of 13 (8-20) days. At the seven days follow-up, patients who had a positive Hospital Anxiety and Depression Scale showed a significantly longer time of intubation (p = 0.048) and length of ICU stay (p = 0.023). At three months, we observed a significant relationship between a positive Hospital Anxiety and Depression Scale and a median value of EuroQol-5D (p = 0.048). At six months, we observed that patients who had a positive Post-Traumatic Symptom Scale were significantly younger than the other group. Findings from the present study suggest that a longer time of intubation and length of ICU stay are associated with a higher level of anxiety and depression immediately after ICU discharge. Follow-up programs are recommended to assess and rehabilitate cognitive function at ICU discharge.

Hospital-Acquired Infections in Critically Ill Patients With COVID-19.

BACKGROUND: Few small studies have described hospital-acquired infections (HAIs) occurring in patients with COVID-19. RESEARCH QUESTION: What characteristics in critically ill patients with COVID-19 are associated with HAIs and how are HAIs associated with outcomes in these patients? STUDY DESIGN AND METHODS: Multicenter retrospective analysis of prospectively collected data including adult patients with severe COVID-19 admitted to eight Italian hub hospitals from February 20, 2020, through May 20, 2020. Descriptive statistics and univariate and multivariate Weibull regression models were used to assess incidence, microbial cause, resistance patterns, risk factors (ie, demographics, comorbidities, exposure to medication), and impact on outcomes (ie, ICU discharge, length of ICU and hospital stays, and duration of mechanical ventilation) of microbiologically confirmed HAIs. RESULTS: Of the 774 included patients, 359 patients (46%) demonstrated 759 HAIs (44.7 infections/1,000 ICU patient-days; 35% multidrug-resistant [MDR] bacteria). Ventilator-associated pneumonia (VAP; n = 389 [50%]), bloodstream infections (BSIs; n = 183 [34%]), and catheter-related BSIs (n = 74 [10%]) were the most frequent HAIs, with 26.0 (95% CI, 23.6-28.8) VAPs per 1,000 intubation-days, 11.7 (95% CI, 10.1-13.5) BSIs per 1,000 ICU patient-days, and 4.7 (95% CI, 3.8-5.9) catheter-related BSIs per 1,000 ICU patient-days. Gram-negative bacteria (especially Enterobacterales) and Staphylococcus aureus caused 64% and 28% of cases of VAP, respectively. Variables independently associated with infection were age, positive end expiratory pressure, and treatment with broad-spectrum antibiotics at admission. Two hundred thirty-four patients (30%) died in the ICU (15.3 deaths/1,000 ICU patient-days). Patients with HAIs complicated by septic shock showed an almost doubled mortality rate (52% vs 29%), whereas noncomplicated infections did not affect mortality. HAIs prolonged mechanical ventilation (median, 24 days [interquartile range (IQR), 14-39 days] vs 9 days [IQR, 5-13 days]; P < .001), ICU stay (24 days [IQR, 16-41 days] vs 9 days [IQR, 6-14 days]; P = .003), and hospital stay (42 days [IQR, 25-59 days] vs 23 days [IQR, 13-34 days]; P < .001). INTERPRETATION: Critically ill patients with COVID-19 are at high risk for HAIs, especially VAPs and BSIs resulting from MDR organisms. HAIs prolong mechanical ventilation and hospitalization, and HAIs complicated by septic shock almost double mortality. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04388670; URL: www.clinicaltrials.gov.

Extracorporeal CO2 Removal by Respiratory Electrodialysis: An In Vitro Study.

We previously described a highly efficient extracorporeal CO2 removal technique called respiratory electrodialysis (R-ED). Respiratory electrodialysis was composed of a hemodiafilter and a membrane lung (ML) positioned along the extracorporeal blood circuit, and an electrodialysis (ED) cell positioned on the hemodiafiltrate. The ED regionally increased blood chloride concentration to convert bicarbonate to CO2 upstream the ML, thus enhancing ML CO2 extraction (VCO2ML). In this in vitro study, with an aqueous polyelectrolytic carbonated solution mimicking blood, we tested a new R-ED setup, featuring an ML positioned on the hemodiafiltrate after the ED, at increasing ED current levels (0, 2, 4, 6, and 8 A). We measured VCO2ML, electrolytes concentrations, and pH of the extracorporeal circuit. Raising levels of ED-current increased chloride concentration from 107.5 ± 1.6 to 114.6 ± 1.3 mEq/L (0 vs. 8 A, p < 0.001) and reduced pH from 7.48 ± 0.01 to 6.51 ± 0.05 (0 vs. 8 A, p < 0.001) of the hemodiafiltrate entering the ML. Subsequently, VCO2ML increased from 27 ± 1.7 to 91.3 ± 1.5 ml/min (0 vs. 8 A, p < 0.001). Respiratory electrodialysis is efficient in increasing VCO2ML of an extracorporeal circuit featuring an ML perfused by hemodiafiltrate. During R-ED, the VCO2ML can be significantly enhanced by increasing the ED current.

Spatial orientation and mechanical properties of the human trachea: a computed tomography study.

BACKGROUND: The literature generally describes the trachea as oriented toward the right and back, but there is very little detailed characterization. Therefore, the aim of this study was to precisely determine the spatial orientation and to better characterize the physical properties of the human trachea. METHODS: We analyzed lung computed tomography scans of 68 intubated and mechanically ventilated subjects suffering from acute lung injury/ARDS at airway pressures (Paw) of 5, 15, and 45 cm H2O. At each Paw, the inner edge of the trachea from the subglottal space to the carina was captured. Tracheal length and diameter were measured. Tracheal orientation and compliance were estimated from processing barycenter and surface tracheal sections. RESULTS: Tracheal orientation at a Paw of 5 cm H2O showed a 4.2 ± 5.3° angle toward the right and a 20.6 ± 6.9° angle downward toward the back, which decreased significantly while increasing Paw (19.4 ± 6.9° at 15 cm H2O and 17.1 ± 6.8° at 45 cm H2O, P < .001). Tracheal compliance was 0.0113 ± 0.0131 mL/cm H2O/cm of trachea length from 5 to 15 cm H2O and 0.004 ± 0.0041 mL/cm H2O/cm of trachea length from 15 to 45 cm H2O (P < .001). Tracheal diameter was 19.6 ± 3.4 mm on the medial-lateral axis and 21.0 ± 4.3 mm on the sternal-vertebral axis. CONCLUSIONS: The trachea is oriented downward toward the back at a 20.6 ± 6.9° angle and slightly toward the right at a 4.2 ± 5.3° angle. Understanding tracheal orientation may help in enhancing postural drainage and respiratory physiotherapy, and knowing the physical properties of the trachea may aid in endotracheal tube cuff design.